Systematically administered opioids activate bulbospinal noradrenergic pathways. The resulting spinally released norepinephrine activates a2-adrenoceptors on cholinergic neurons, causing ACh release and inhibition of spinal transmission of noxious sensory information. This hypothesis suggests that i.t. neostigmine, by enhancing spinal cholinergic activity, should potentiate analgesia from intraspinal a-adrenergic agonist and from systemic opioids.